(1.3)--新冠病毒的传播和致病途径.pdf

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1、ReviewMechanisms of SARS-CoV-2 Transmissionand PathogenesisAndrew G.Harrison,1,2Tao Lin,1,2and Penghua Wang1,*The emergence of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)marks the third highly pathogenic coronavirus to spill over into the humanpopulation.SARS-CoV-2 is highly transmis

2、sible with a broad tissue tropism that islikely perpetuating the pandemic.However,important questions remain regardingits transmissibility and pathogenesis.In this review,we summarize current SARS-CoV-2 research,with an emphasis on transmission,tissue tropism,viral pathogen-esis,and immune antagonis

3、m.We further present advances in animal models thatare important for understanding the pathogenesis of SARS-CoV-2,vaccine devel-opment,and therapeutic testing.When necessary,comparisons are made fromstudies with SARS to provide further perspectives on coronavirus infectiousdisease 2019(COVID-19),as

4、well as draw inferences for future investigations.The Emergence of a Third,Novel CoronavirusCurrent State of the COVID-19 PandemicCoVs have caused three large-scale outbreaks over the past two decades:severe acute respira-tory syndrome(SARS),Middle Eastern respiratory syndrome(MERS),and now COVID-19

5、.Theorigin of the COVID-19 pandemic was traced back to a cluster of pneumonia cases connectedto a wet seafood market in Wuhan City,Hubei Province,China 1.Following the likely spilloverof a zoonotic disease(see Glossary),further work confirmed the etiological agent to be anovel Betacoronavirus relate

6、d to SARS-CoV 1,2.The first patients developed symptoms onDecember 1,2019 after which rapid human-to-human transmission and intercontinental spreadlater ensued,being declared a pandemic by the WHO in March 2020 3.Since then,35 millionpeople have been infected with SARS-CoV-2,with 1 million deaths in

7、 235 countries,areas,orterritories 4.Although SARS-CoV-2 appears to be less lethal than SARS-CoV or MERS-CoV,its transmissibility is higher.To find solutions to contain this raging pandemic,global researchefforts have been quickly mobilized,each day resulting in new advances in basic and clinicalres

8、earch,therapy,diagnosis,vaccine and drug development,as well as epidemiology.Here,we conduct a comprehensive review of the current state of COVID-19 research,with a principalfocus on the mechanisms of transmission and pathogenesis of SARS-CoV-2 stemming fromclinical and animal studies.SARS-CoV-2 Cha

9、racteristicsSARS-CoV-2 Genome and StructureCoVs of the family Coronaviridae are enveloped,positive-sense single-stranded RNA viruses 5.All of the highly pathogenic CoVs,including SARS-CoV-2,belong to the Betacoronavirus genus,group 2 5.The SARS-CoV-2 genome sequence shares 80%sequence identity with

10、SARS-CoV and 50%with MERS-CoV 1,6.Its genome comprises 14 open reading frames(ORFs),two-thirdsofwhichencode16nonstructuralproteins(nsp116)thatmakeupthereplicasecom-plex 6,7.The remaining one-third encodes nine accessory proteins(ORF)and four structuralproteins:spike(S),envelope(E),membrane(M),and nu

11、cleocapsid(N),of which Spike mediatesSARS-CoV entry into host cells 8.However,the S gene of SARS-CoV-2 is highly variable fromHighlightsThe emergence of SARS-CoV-2 fromChinaand therapidity of a worldwidepandemichaspromotedglobalcollaboration,built on a body of workestablished from previous SARS-CoVa

12、nd MERS-CoV outbreaks.These pastexperiences have aided the swiftnessby which the research community hasresponded with an astonishing body ofwork.SARS-CoV-2 is a novel virus in theBetacoronavirus genus and exhibitssimilarities to SARS-CoV in genomestructure,tissue tropism,and viralpathogenesis.Yet,SA

13、RS-CoV-2 ap-pears to be more transmissible andthe diversity of immune responsesare poorly understood.Highly pathogenic coronaviruses displaypotent interferon(IFN)antagonism,which is evident in cases of severeCOVID-19 with reduced IFN signaling,and an overaggressive immune re-sponse compounded by hei

14、ghtenedcytokines/chemokines.Animal models for SARS-CoV-2 reca-pitulate important aspects of humanCOVID-19 that are essential for evalu-ating current and prospective antiviraltherapeutics and vaccine candidates.1Department of Immunology,School ofMedicine,University of ConnecticutHealth Center,Farming

15、ton,CT 06030,USA2These authors contributed equally.*Correspondence:pewanguchc.edu(P.Wang).1100Trends in Immunology,December 2020,Vol.41,No.12https:/doi.org/10.1016/j.it.2020.10.004 2020 Elsevier Ltd.All rights reserved.Trends in ImmunologySARS-CoV,sharing1);by contrast,the corresponding estimates fo

16、r SARS-CoV were approximatelyzero 49.Similarly,asymptomatic spread of SARS-CoV-2 has been documented throughoutthe course of the pandemic 48,51,5356.Understanding the relative importance of cryptictransmission to the current COVID-19 pandemic is essential for public health authorities tomake the mos

17、t comprehensive and effective disease control measures,which include mask-wearing,contact tracing,and physical isolation.For SARS-CoV-2,various modes of transmission have been proposed,including aerosol,surfacecontamination,and the fecaloral route,representing confounding factorsinthe current COVID-

18、19pandemic;thus,their relative importance is still being investigated(Figure 2)57.Aerosol trans-mission(spread 1 m)was implicated in the Amoy Gardens outbreak during the SARScomprising primarily DNA fromneutrophils due to chromatindecondensation,which can trapextracellular pathogens.Pattern recognit

19、ion receptor:germline-encoded host sensor thatrecognizes a signature pattern inmicrobial molecules.Prodromal period:time immediatelyfollowing the incubation period of amicrobialinfectioninwhichahostbeginsto experience symptoms or changes inbehavior/functioning.Prothrombin time:measurement ofthe extr

20、insic pathway of coagulation.Reproductive number(R0):expectednumberofnewdiseasecasesgeneratedby one case.R01 indicates that theoutbreak will expand;R05 m)is the most pronounced and heavily implicated mode of transmission reported during thepandemic.Direct contact spread from one infected individual

21、to a second,nave person has also been considered a driverof human-to-human transmission,especially in households with close interactions between family members.Thecontagiousness of SARS-CoV-2 after disposition on fomites(e.g.,door handles)is under investigation,but is likely acompounding factor for

22、transmission events,albeitless frequently than droplet or contact-driven transmission.Both airborneand fecaloral human-to-human transmission events were reported in the precursor SARS-CoV epidemic but have yet to beobserved in the current crises.Solid arrows show confirmed viral transfer from one in

23、fected person to another,with a declin-inggradientinarrowwidthdenotingtherelativecontributionsofeachtransmissionroute.Dashedlinesshowtheplausibilityoftransmission types that have yet to be confirmed.SARS-CoV-2 symbol in infected patient indicates where RNA/infectiousvirus has been detected 43,44,474

24、9,57,59,60.Figure generated with BioRender.Trends in Immunology1104Trends in Immunology,December 2020,Vol.41,No.12Age-Associated COVID-19 SeverityIt is widely accepted that the aging process predisposes individuals to certain infectious dis-eases 68.In the case of COVID-19,older age is associated wi

25、th greater COVID-19 morbidity,admittance to the intensive care unit(ICU),progression to ARDS,higher fevers,and greatermortality rates 6971.Moreover,lymphocytopenia,neutrophilia,elevated inflammation-related indices,and coagulation-related indicators have been consistently reported in older(65-years

26、old)relative to young and middle-aged patients with COVID-19(Table 1)46,65,7175.At the cellular level,a lower capacity of CD4+and CD8+T-cells to produceIFN-and IL-2,as well as an impairment in T-cell activation from dendritic cells(DCs)inpatients with acute COVID-19(55-years old)could compromise an

27、optimal adaptive immuneresponse 76.Based on examples from mice,a productive CD4+T-cell response reliesheavily on lung-resident DCs(rDCs)and abates SARS-CoV infection 77,78.However,whether a reduction in the DC population in the lungs of older patients with more severeCOVID-19 causes suboptimal T-cel

28、l activation during SARS-CoV-2 infection remains to be ro-bustly investigated.TrendsTrends inin ImmunologyImmunologyFigure 3.Clinical Symptoms of Coronavirus Infectious Disease 2019(COVID-19).COVID-19 manifestations inhumans have been described to incorporate multiple body systems with varying degre

29、es of onset and severity.Both theupper respiratory tract and lower respiratory tract manifestations are often the most noticeable if a patient is notasymptomatic,in addition to systemic symptoms that are the most frequently reported regardless of disease severity.Red-highlighted signs/symptoms tend

30、to be over-represented in severe patients,but common symptoms are also present inmore advanced COVID-19.A severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)virus symbol denotes wherea live virus and/or viral RNA has been isolated.Abbreviation:ARDS:acute respiratory distress syndrome 37,46,4

31、8,66,139.Figure generated with BioRender.Trends in ImmunologyTrends in Immunology,December 2020,Vol.41,No.121105Higher proportions of proinflammatory macrophages and neutrophils have also been observedin the bronchoalveolar lavage fluid(BALF)of COVID-19 patients with severe symptomscompared with tho

32、se exhibiting mild symptoms(Figure 4,Key Figure)79.Accordingly,pro-inflammatory cytokines(e.g.,IL-6 and IL-8)are elevated in the BALF of patients with severeCOVID-19,along with higher expression of inflammatory chemokines(e.g.,CCL2)in macro-phages relative to patients with nonsevere COVID-19 7982.In

33、deed,similar inflammatorymilieux have been associated with severe lung pathology in patients with SARS,along with thenotable cytokine storm that can present in patients critically ill with COVID-19 71,8387.These proinflammatory mediators can,in turn,perpetuate lung disease by elevating C-reactivepro

34、tein(CRP)from the liver(Table 1)through signal transducer and activator of transcription3(STAT3)-IL-6 signaling 88.Therefore,an increase in CRP concentrations can correlate withelevated serum IL-6 production observed in patients with COVID-19 79,80,88.From anotherangle,formation of neutrophil extrac

35、ellular traps(NETs)inside microvessels is pronouncedin patients with severe relative to mild COVID-19,implicating NETs as possible potentiators ofCOVID-19 pathogenesis 89.The recruitment of these activated neutrophils and monocytesmay be driven by pulmonary endothelial cell dysfunction through vascu

36、lar leakage,tissueedema,endotheliitis,and possibly,disseminated intravascular coagulation(DIC)pathways;indeed,a recent study demonstrated direct SARS-CoV-2 infection of vascular endothelial cellswith concomitant accumulation of inflammatory mononuclear cells(e.g.,neutrophils)in multipleorgans(lung,h

37、eart,kidney,small bowel,and liver)in patients with severe COVID-19(Figure 4)Table 1.Common Laboratory Indices and Radiological Findings from Patients with COVID-19Laboratory findingsCOVID-19 studyaRefs6514014113773138Patient populationMiddle-aged,hospitalized;N=99Middle-aged,hospitalized/ICU;N=1099E

38、lderly,mild-severeN=71Middle-aged,hospitalized adults;N=140Elderly,deceased;N=82Young,milddisease;N=46Ground-glassopacities1456.4b10099.3-63Pneumonia(unilateral or bilateral)c10091.173-93.9-Lymphocytopenia35(1.13.2 109/ml)83.2(1500/mm3)37(1200/l)75.489.2(1.0 109/l)63(1.5109/l)Leukopenia9(3.59.5x109/

39、ml)33.7(4000/mm3)21(4000/l)19.6(3.59.5109/ml)21.7(4109/l)Thrombocytopenia12(125350109/ml)36.2(150 000/mm3)10(15104/l)-24.3(100 109/l)21.7(6.3 109/l)-dC-reactive protein(mg/l)86(05)60.7(10)59(1030)91.9(03)100(10)19.6(10)Alanineaminotransferase(U/l)28(950)21.3(40)18(45)-30.6(40)15.2(40)D-dimer(g/l)36(

40、01.5)46.4(500)-43.2(0243)97.1(550)15.2(500)Prothrombin time(s)5(10.513.5)-100(12.314.3)e-aValues for each laboratory manifestation represent the percentage of patients with that clinical finding above or below the normal range(listed below in brackets);dashedlines indicate measurements not taken dur

41、ing referenced study.bPercentage of patients with lung ground-glass opacity on a chest CT scan(technique specifically denoted in original study).cPneumonia was not always definitively mentioned in studies,albeit lung manifestations were commonly recorded.d denotes an elevation of measured indices ab

42、ove reference value for those percentage of patientseOver the past 24 h,leading up to death,all 13 patients who were included for this metric had a prothrombin time of 12.1 s.Trends in Immunology1106Trends in Immunology,December 2020,Vol.41,No.1290.In fact,many patients with COVID-19 have met the DI

43、C case definition based on elevatedserum D-dimer amounts and prolonged prothrombin times 91,92.Together,it is reasonableto assumethatdirectviralinsultand immune cell recruitment escalate endothelial contractilityandthe loosening of gap junctions,thus promoting vascular leakage and the systemic impai

44、rment ofthe circulatory system in this pathology.Key FigureA Brief Overview of Lung Pathology in Patients with Coronavirus Infectious Disease 2019(COVID-19)TrendsTrends inin ImmunologyImmunologyFigure 4.Following inhalation of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)into the respi

45、ratory tract,the virus traverses deep into the lower lung,where it infects a range of cells,including alveolar airway epithelial cells,vascular endothelial cells,and alveolar macrophages.Upon entry,SARS-CoV-2 is likelydetected by cytosolic innate immune sensors,as well as endosomal toll-like recepto

46、rs(TLRs)that signal downstream to produce type-I/III interferons(IFNs)andproinflammatory mediators.The high concentration of inflammatory cytokines/chemokines amplifies the destructive tissue damage via endothelial dysfunction andvasodilation,allowing the recruitment of immune cells,in this case,mac

47、rophages and neutrophils.Vascular leakage and compromised barrier function promoteendotheliitis and lung edema,limiting gas exchange that then facilitates a hypoxic environment,leading to respiratory/organ failure.The inflammatory milieu inducesendothelial cells to upregulate leukocyte adhesion mole

48、cules,thereby promoting the accumulation of immune cells that may also contribute to the rapid progression ofrespiratory failure.Hyperinflammation in the lung further induces transcriptional changes in macrophages and neutrophils that perpetuate tissue damage that ultimatelyleads to irreversible lun

49、g damage.Recent evidence suggests that systemic inflammation induces long-term sequela in heart tissues 66,79,80,82,84,87,90,95.Abbreviations:BALF,bronchoalveolar lavage fluid;IRF3,interferon regulatory factor 3;NF-B,nuclear factor-B;RIG-I,retinoic acid-inducible gene I;STAT1/2,signaltransducer and

50、activator of transcription 1/2;STING,Stimulator of interferon genes.Figure generated with BioRender.Trends in ImmunologyTrends in Immunology,December 2020,Vol.41,No.121107SARS-CoV-2 Innate Immune Evasion Strategies:Examples from other Betacoronavirus InfectionsTherecognitionofvirusinfectionbeginswit